Curcumin and cancer: An “old-age” disease with an “age-old” solution

Cancer is a hyperproliferative disorder that is usually treated by chemotherapeutic agents that are toxic not only to tumor cells but also to normal cells, so these agents produce major side effects. In addition, these agents are highly expensive and thus not affordable for most. Moreover, such agents cannot be used for cancer prevention. Traditional medicines are generally free of the deleterious side effects and usually inexpensive. Curcumin, a component of turmeric (Curcuma longa), is one such agent that is safe, affordable, and efficacious. How curcumin kills tumor cells is the focus of this review. We show that curcumin modulates growth of tumor cells through regulation of multiple cell signaling pathways including cell proliferation pathway (cyclin D1, c-myc), cell survival pathway (Bcl-2, Bcl-xL, cFLIP, XIAP, c-IAP1), caspase activation pathway (caspase-8, 3, 9), tumor suppressor pathway (p53, p21) death receptor pathway (DR4, DR5), mitochondrial pathways, and protein kinase pathway (JNK, Akt, and AMPK). How curcumin selectively kills tumor cells, and not normal cells, is also described in detail.

/pdf/curcumin-and-cancer-cells-how-many-ways-can-curry-kill-tumor-4h4z2cuv33.pdf

Curcumin and cancer cells: how many ways can curry kill tumor cells selectively?

Throughout history, natural products have afforded a rich source of compounds that have found many applications in the fields of medicine, pharmacy and biology. Within the sphere of cancer, a number of important new commercialised drugs have been obtained from natural sources, by structural modification of natural compounds, or by the synthesis of new compounds, designed following a natural compound as model. The search for improved cytotoxic agents continues to be an important line in the discovery of modern anticancer drugs. The huge structural diversity of natural compounds and their bioactivity potential have meant that several products isolated from plants, marine flora and microorganisms can serve as “lead” compounds for improvement of their therapeutic potential by molecular modification. Additionally, semisynthesis processes of new compounds, obtained by molecular modification of the functional groups of lead compounds, are able to generate structural analogues with greater pharmacological activity and with fewer side effects. These processes, complemented with high-throughput screening protocols, combinatorial chemistry, computational chemistry and bioinformatics are able to afford compounds that are far more efficient than those currently used in clinical practice. Combinatorial biosynthesis is also applied for the modification of natural microbial products. Likewise, advances in genomics and the advent of biotechnology have improved both the discovery and production of new natural compounds.

Natural products as leads to anticancer drugs.

Background
Zinc oxide nanoparticles (ZnO NPs) have received much attention for their implications in cancer therapy. It has been reported that ZnO NPs induce selective killing of cancer cells. However, the underlying molecular mechanisms behind the anticancer response of ZnO NPs remain unclear.

http://fac.ksu.edu.sa/sites/default/files/5_0.pdf

Zinc oxide nanoparticles selectively induce apoptosis in human cancer cells through reactive oxygen species.

This review addresses the oncopharmacological properties of curcumin at the molecular level. First, the interactions between curcumin and its molecular targets are addressed on the basis of curcumin's distinct chemical properties, which include H-bond donating and accepting capacity of the β-dicarbonyl moiety and the phenylic hydroxyl groups, H-bond accepting capacity of the methoxy ethers, multivalent metal and nonmetal cation binding properties, high partition coefficient, rotamerization around multiple C-C bonds, and the ability to act as a Michael acceptor. Next, the in vitro chemical stability of curcumin is elaborated in the context of its susceptibility to photochemical and chemical modification and degradation (e.g., alkaline hydrolysis). Specific modification and degradatory pathways are provided, which mainly entail radical-based intermediates, and the in vitro catabolites are identified. The implications of curcumin's (photo)chemical instability are addressed in light of pharmaceutical curcumin preparations, the use of curcumin analogues, and implementation of nanoparticulate drug delivery systems. Furthermore, the pharmacokinetics of curcumin and its most important degradation products are detailed in light of curcumin's poor bioavailability. Particular emphasis is placed on xenobiotic phase I and II metabolism as well as excretion of curcumin in the intestines (first pass), the liver (second pass), and other organs in addition to the pharmacokinetics of curcumin metabolites and their systemic clearance. Lastly, a summary is provided of the clinical pharmacodynamics of curcumin followed by a detailed account of curcumin's direct molecular targets, whereby the phenotypical/biological changes induced in cancer cells upon completion of the curcumin-triggered signaling cascade(s) are addressed in the framework of the hallmarks of cancer. The direct molecular targets include the ErbB family of receptors, protein kinase C, enzymes involved in prostaglandin synthesis, vitamin D receptor, and DNA.

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

Curcumin induces apoptosis through mitochondrial hyperpolarization and mtDNA damage in human hepatoma G2 cells.

Sterigmatocystin-induced oxidative DNA damage in human liver-derived cell line through lysosomal damage.

The role of oxidative stress in DNA damage in pancreatic β cells induced by di-(2-ethylhexyl) phthalate.

Background: Hypertension has been associated with cognitive dysfunction in the general population and patients with Alzheimer’s disease (AD). However, there are contradictory data regarding the potential association between hypertension and diagnosis of Parkinson’s disease (PD), the second most common neurodegenerative disorder after AD. The purpose of this meta-analysis is to synthesize data from cohort studies to explore the potential association between pre-existing hypertension and subsequent PD diagnosis. Methods: The PubMed and Embase databases were searched to identify all relevant studies. Two independent investigators performed the data extraction. Eligible cohort studies providing risk and precision estimates related to hypertension and PD were selected. Pooled risk ratios (RRs) with 95% confidence interval (CI) were calculated by using a random-effects or a fixed-effects model. Sensitivity analyses after excluding one study at a time were performed to assess the stability of the results. Publication bias was assessed with Begg’s test and Egger’s test. Results: Seven cohort studies were identified, including 3170 persons who were confirmed to have developed PD and 339517 participants who did not have PD during follow-up. The onset of hypertension prior to PD diagnosis was significantly associated with an increased risk of motor stage PD (RR=1.799, 95% CI [1.066–3.037]). This relationship was further confirmed by secondary analyses based on estimates adjusted for potential vascular confounders (RR=1.319, 95% CI [1.073–1.622]). After excluding one study at a time, the sensitivity analyses still showed that hypertension history was significantly associated with an increased risk of motor stage PD (RR with 95% CI ranging from 1.11[1.075-1.35] to 1.42 [1.65-1.83]). No publication bias was observed in this meta-analysis. Conclusion: The findings of this meta-analysis suggest that hypertension may be a risk factor for motor stage PD, which may provide novel insights into the etiology and pathogenesis of this neurodegenerative disorder. However, large-scale well-designed studies that consider various confounders are still needed to further verify and clarify the association between hypertension and PD diagnosis.

/pdf/hypertension-and-diagnosis-of-parkinson-s-disease-a-meta-2lcb3ksnj0.pdf

Qiujuan Li

Papers

Curcumin induces apoptosis through mitochondrial hyperpolarization and mtDNA damage in human hepatoma G2 cells.

Sterigmatocystin-induced oxidative DNA damage in human liver-derived cell line through lysosomal damage.

The role of oxidative stress in DNA damage in pancreatic β cells induced by di-(2-ethylhexyl) phthalate.

Hypertension and Diagnosis of Parkinson’s Disease: A Meta-Analysis of Cohort Studies

ROS-dependent Atg4 upregulation mediated autophagy plays an important role in Cd-induced proliferation and invasion in A549 cells.